The present invention concerns devices and methods for transdermal delivery or transport of therapeutic agents by electrotransport. Herein the term "electrotransport" is used to refer to methods and apparatus for transdermal delivery of therapeutic agents, whether charged or uncharged, by means of an applied electromotive force to an agent-containing reservoir. The particular therapeutic agent to be delivered may be completely charged (ie, 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, s electroosmosis or a combination of the two. In general, electroosmosis of a therapeutic species into a tissue results from the migration of solvent, in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir. Still another type of electrotransport process, electroporation, involves the formation of transiently-existing pores in a biological membrane by the application of an electric field, through which pores an agent can be delivered either passively (ie, without electrical assistance) or actively (ie, under the influence of an electric potential). However, in any given electrotransport process, more than one of these processes may be occurring simultaneously to a certain extent. Accordingly, the term "electrotransport", as used herein, should be given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged, or a mixture thereof, regardless of the specific mechanism or mechanisms by which the agent actually is transported.
Iontophoretic devices have been known since the early 1900's. British patent specification No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be immobilized near such source. The device of that British specification was made by forming a galvanic cell from the electrodes and the material containing the medicament or drug to be delivered transdermally. The galvanic cell produced the current necessary for iontophoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
More recently, a number of United States patents have issued in the electrotransport field, indicating a renewed interest in this mode of drug delivery. For example, Vernon et al U.S. Pat. No. 3,991,755; Jacobsen et al U.S. Pat. No. 4,141,359; Wilson U.S. Pat. No. 4,398,545; and Jacobsen U.S. Pat. No. 4,250,878 disclose examples of electrotransport devices and some applications thereof. The electrotransport process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs. Perhaps the most common use of electrotransport is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
In presently known electrotransport devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by electrotransport. The other electrode, called the counter, indifferent, inactive or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, eg, a battery. For example, if the ionic substance to be delivered into the body is positively charged (ie, a cation), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (ie, an anion), then the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge, or drugs of neutral charge, into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anode can deliver a cationic or neutrally charged substance into the body while the cathode can deliver an anionic or neutrally charged substance into the body.
Furthermore, existing electrotransport devices generally require a reservoir or source of the beneficial agent (which is preferably an ionized or ionizable agent or a precursor of such agent) to be delivered into the body. Examples of such reservoirs or sources of agents include a pouch as described in the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, or a pre-formed gel body as described in Webster U.S. Pat. No. 4,383,529 and Ariura et al U.S. Pat. No. 4,474,570. Such drug reservoirs are electrically connected to the anode or the cathode of an electrotransport device to provide a fixed or renewable source of one or more desired agents.
More recently, electrotransport delivery devices have been developed in which the donor and counter electrode assemblies have a "multi-laminate" construction. In these devices, the donor and counter electrode assemblies are formed of multiple layers of (usually) polymeric matrices. For example, Parsi U.S. Pat. No. 4,731,049 discloses a donor electrode assembly having hydrophilic polymer based electrolyte reservoir and drug reservoir layers, a skin-contacting hydrogel layer, and optionally one or more semipermeable membrane layers. Sibalis U.S. Pat. No. 4,640,689 discloses in FIG. 6 an electrotransport delivery device having a donor electrode assembly comprised of a donor electrode (204), a first drug reservoir (202), a semipermeable membrane layer (200), a second drug reservoir (206), and a microporous skin-contacting membrane (22'). The electrode layer can be formed of a carbonized plastic, metal foil or other conductive films such as a metallized mylar film. In addition, Ariura et al, U.S. Pat. No. 4,474,570 discloses a device wherein the electrode assemblies include a conductive resin film electrode layer, a hydrophilic gel reservoir layer, a current distribution and conducting layer and an insulating backing layer. Ariura et al disclose several different types of electrode layers including an aluminum foil electrode, a carbon fiber non-woven fabric electrode and a carbon-containing rubber film electrode.
Transdermal electrotransport delivery devices having electrodes composed of electrochemically inert materials, as well as devices having electrodes composed of electrochemically reactive materials, are known. Examples of electrochemically inert electrode materials include platinum, carbon, gold and stainless steel. Unfortunately, the use of electrochemically inert electrode materials can cause protons and oxygen gas, or alternatively hydroxyl ions and hydrogen gas, to be produced at the electrode surface through hydrolysis of water. The prior art has also recognized that the use of sacrificial (ie, electrochemically reactive) electrodes can avoid the pH changes and gas generation effects associated with the hydrolysis of water which generally accompanies the use of electrodes made from electro-chemically inert materials. Electrotransport delivery devices with sacrificial electrodes are disclosed in Phipps et al U.S. Pat. Nos. 4,744,787 and 4,747,819 and Petelenz et al U.S. Pat. No. 4,752,285, incorporated herein by reference in their entirety. These patents disclose electrotransport electrodes composed of materials which are either oxidized or reduced during operation of the device. Particularly preferred electrochemically reactive electrode materials include silver as the anodic electrode, and silver chloride as the cathodic electrode. One potential disadvantage of these electrochemically reactive electrodes, is that once they are oxidized or reduced, they produce extraneous ions of the same charge as the drug ions. The extraneous ions can compete with the drug ions for carrying current from the device into the body, thereby lowering the drug delivery efficiency of the device. For example, when using a silver anode to deliver a cationic drug, the operation of the device causes the silver electrode to be oxidized according to the following reaction: EQU Ag.fwdarw.Ag.sup.+ +e.sup.-
If left to freely migrate, the silver ions produced in the oxidation reaction will compete with the drug cations for delivery into the body. U.S. Pat. Nos. 4,744,787; 4,747,819; and 4,752,285 deal with the problem of extraneous silver ions by compounding the drug as a chloride or hydrochloride salt. The silver ions react with the drug counter ions (ie, chloride ions) to produce silver chloride which is substantially insoluble in water, thereby removing the extraneous silver ions from solution. Since many drugs are manufactured and sold in hydrochloride salt forms, this represents a practical solution to the problem of extraneous silver ions produced during oxidation of a silver anode.
Unfortunately, the extraneous ions generated by reduction of silver chloride cathode are not so practically controlled. When a silver chloride cathodic electrode is used to deliver a drug (eg, an anionic drug), the operation of the device causes the silver chloride electrode to be reduced according to the following reaction: EQU AgCl+e.sup.- .fwdarw.Ag+Cl.sup.-
If left to freely migrate, the extraneous chloride ions produced during reduction of the silver chloride electrode will compete with the drug (eg, drug anions) for delivery into the body. Most anionic drug salts are formulated as alkali metal salts or alkaline earth metal salts, most typically as sodium salts. Since most alkali metal chloride and alkaline earth metal chloride salts have good water solubility, the extraneous chloride ions produced by the cathodic reduction do not combine with the drug counter ions to form an insoluble compound. VVhile silver chloride is a substantially water insoluble chloride salt, in practice, anionic drugs which are commercially available are not formulated in the form of a silver salt.
One disadvantage of using the drug counter ion (eg, compounding a cationic drug as a hydrochloride salt or compounding an anionic drug as a silver salt) in order to control extraneous ions produced by oxidation or reduction reactions (eg, oxidation of a silver anode or reduction of a silver chloride cathode), is the fixed supply of drug counter ion which can be placed in the system. Under certain conditions of operation, the amount of free chloride counter ions (or free silver counter ions) may be insufficient to bind all of the extraneous ions being produced by oxidation/reduction at the electrode. Thus, under certain conditions of operation, the electrode/drug salt formulation disclosed in the Phipps et al and Petelenz patents may not be able to effectively remove all of the extraneous ions, eventually resulting in a lowered drug delivery efficiency from the device.
An alternative approach to avoiding the adverse effects associated with extraneous ions produced at the donor electrode of an electrotransport delivery device is disclosed in Sanderson et al, U.S. Pat. No. 4,722,726. This patent discloses an electrode assembly having an upper chamber filled with a salt solution and a lower chamber containing the drug solution. The upper chamber is separated from the lower chamber by means of an ion exchange membrane. The ion exchange membrane is impermeable to the passage of drug ions and ions having the same charge as the drug ions and thereby prevents the drug from entering the upper chamber. Likewise, the membrane prevents ions produced at the electrode surface which have the same charge as the drug ions (ie, either protons or hydroxyl ions in the case of an electrochemically inert electrodes, or metal ions such as silver ions or halide ions such as chloride ions in the case of an electrochemically reactive electrode material) from entering the lower chamber and competing with the drug ions for delivery into the body.
Accordingly, it is an objective of the present invention to provide an electrotransport agent delivery device having a cathodic electrode assembly adapted to deliver an agent such as a drug.
It is a further objective of the present invention to provide a reducible cathodic electrode assembly which effectively controls the production of extraneous anions and which therefore exhibits good drug delivery efficiency.